Catheter lock solution formulations

ABSTRACT

A liquid excipient is added to a lock solution formulation containing a lower alcohol and an anti-coagulant, antibiotic, and/or anti-microbial, such as the ethanol and tri-sodium citrate lock solution formulation, to prevent citrate from crystallizing in catheters made from silicone. The locking solution could include a liquid excipient, such as glycerol, polysorbate-20, or polyethylene glycol (PEG)-400, along with a lower alcohol, such as ethanol, and an anti-coagulant, such as tri-sodium citrate, antibiotic, and/or anti-microbial.

CROSS-REFERENCE TO RELATED APPLICATION

The present application claims the benefit of U.S. ProvisionalApplication Ser. No. 61/908,438 filed Nov. 25, 2013, the entiredisclosure of which is expressly incorporated herein by reference.

FIELD

The present disclosure relates to locking solutions for a catheter, andmore particularly to locking solutions that prevent occlusion.

BACKGROUND

Implanted catheters enjoy widespread use in a number of medicalprocedures. For example, intravenous (IV) therapy relies on long-termimplantation of a venous catheter to deliver fluids, medications, andother substances to a patient. Hemodialysis and hemofiltration both relyon separate draw and return catheters implanted in a vein to allowextracorporeal treatment of the blood. Peritoneal dialysis, in contrast,relies on a single catheter implanted in the peritoneum to permitintroduction and withdrawal of dialysate to permit in situ dialysis.

The need to leave catheters implanted over long periods of time raises anumber of concerns. For example, the catheters can become infectedrequiring treatment of the patient and often times removal of thecatheter. This is a particular problem with transcutaneous catheterswhere the skin penetration is a common route of infection. In addition,implanted catheters can often become plugged or fouled over time. Thisis a particular problem with intravascular catheters where clotting andthrombus formation within the catheter lumen can be problematic.

To reduce problems associated with thrombus formation and to maintainthe patency of catheters, it is now common to “lock” catheters betweensuccessive uses. Locking typically involves first flushing the catheterwith saline to remove blood and other substances from the catheterlumen. After the catheter has been flushed, an anti-coagulant solution,such as heparin, is then injected to displace the saline and fill thelumen. The heparin-locking solution both excludes blood from the lumenand actively inhibits clotting and thrombus formation within the lumen.While some thrombus may still form at the distal tip of the catheter,the formation is usually minimal. It has further been proposed tocombine various anti-microbial, bactericidal, or bacteriostaticsubstances with the locking solution in order to inhibit infection atthe same time that thrombus is being inhibited.

While generally effective, the use of heparin locks suffers from anumber of disadvantages. The need to prepare a heparin solution at theend of every catheter treatment session is time-consuming and presentsan opportunity for a caregiver to commit an error. Hemodialysis andhemofiltration patients will have to undergo such heparin locks at leastseveral times a week, while patients on IV may have to undergo suchheparin locks several times a day. Over time, heparin locks areinconvenient and expensive. Moreover, the need to combine a separateanti-microbial agent in the heparin lock solution further complicatesthe procedure and adds expense, and the addition of an anti-microbialagent to the heparin lock will generally be effective only within thelumen and at the openings from the lumen. There will be little reductionin the risk of infection in the regions surrounding the implantedcatheter, including at the point of penetration through the skin wherethe risk of infection is the greatest.

A lock solution formulation containing ethanol and tri-sodium citrateprovides anti-coagulant and disinfection properties. However, cathetersmade with silicone elastomers, due to their very high moisture andalcohol permeability, as well as catheters made of other permeablematerials, could become blocked due to crystallized citrate lodged insome segments of the catheters, causing occlusion.

It would be desirable to improve lock solution formulations containing alower alcohol and an anti-coagulant, antibiotic, and/or anti-microbial,such as the ethanol tri-sodium citrate formulation, to prevent suchblocking while maintaining their performances.

SUMMARY

The present disclosure provides solutions for improved locking and/ordisinfection of catheters. Excipients are added to a lock solutionformulation containing a lower alcohol and an anti-coagulant,antibiotic, and/or anti-microbial, such as the ethanol and tri-sodiumcitrate lock solution formulation, to prevent citrate from crystallizingin catheters made from silicone.

The locking solution could include a liquid excipient, such as glycerol,polysorbate-20, or polyethylene glycol (PEG)-400, along with a loweralcohol, such as ethanol, and an anti-coagulant, such as tri-sodiumcitrate, antibiotic, and/or anti-microbial.

In one aspect, the locking composition for a catheter includes at leastone lower alcohol, at least one anti-coagulant compound, and at leastone liquid excipient at a sufficient concentration to minimize the atleast one anti-coagulant compound from crystallizing. In another aspect,a locking composition for an implantable silicone catheter includes alower alcohol, an anti-coagulant compound, and an excipient, wherein theexcipient is present in the amount of at least about 0.5% by weight ofthe locking composition.

In another aspect, a method of preventing crystallization in animplantable silicone catheter is provided. The method includesintroducing a locking composition into a lumen of the implantablesilicone catheter, wherein the locking composition includes a loweralcohol, having one to four carbon atoms, an anti-coagulant compound,and an excipient, wherein the excipient is present in the amount of atleast about 0.5% by weight of the locking composition.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing features of the present disclosure will be apparent fromthe following Detailed Description, taken in connection with theaccompanying drawings, in which:

FIG. 1 shows a sphygmomanometer connected to a syringe;

FIG. 2 shows a catheter tubing with a gel-like plug;

FIG. 3 shows a catheter tubing with a recoiling liquid/bubble;

FIG. 4 shows a Groshong 4Fr catheter after 1 day; and

FIG. 5 shows a Groshong 4Fr catheter after 14 days.

DETAILED DESCRIPTION

The present disclosure is directed to catheter lock solutions includinga lower alcohol combined with a functional compound such as ananti-coagulant, antibiotic, and/or anti-microbial; and an excipient. Thecatheter lock solution could include ethanol, tri-sodium citrate, and anexcipient. The term “lock solution,” as used herein, refers to asolution that is introduced (e.g., injected) into a lumen of a catheterand is, at least partially, allowed to remain in the lumen until accessto the lumen is needed. Generally, such solutions provide anti-coagulantand antibacterial properties to an implanted catheter as the solutionremains in the catheter between uses.

The lower alcohol is effective in inhibiting fouling, plugging, andinfection of the lumen of indwelling catheters. As used herein, the term“lower alcohol” refers to an alcohol having one to four carbon atoms.Exemplary lower alcohols include, but are not limited to, ethanol,propanol, isopropanol, butanol, and combinations thereof.

Exemplary anticoagulants include, but are not limited to, riboflavin,sodium citrate, ethylene diamine tetraacetic acid, heparin, lowmolecular weight heparin, citric acid, etc. Exemplary antimicrobialsinclude, but are not limited to, taurolidine, triclosan, chlorhexidine,etc. Exemplary antibiotics include, but are not limited to, gentamicin,vancomycin, etc.

A lock solution containing a lower alcohol and an anti-coagulant isdisclosed in U.S. Pat. No. 6,685,694, the disclosure of which isincorporated herein by reference in its entirety. The entire disclosuresof related U.S. Pat. Nos. 6,592,564 and 6,679,870 are also incorporatedherein by reference.

The excipient could be any suitable agent that upon addition to a loweralcohol, such as ethanol, and an anti-coagulant, such as tri-sodiumcitrate, antibiotic, and/or anti-microbial, prevents or minimizes thefunctional compound from forming a plug or occluding or crystallizing incatheters made from silicone or other permeable materials such as rubber(dimethylsilicone rubber, nitrile rubber, and natural rubber). Byoccluding what is meant is a blockage in flow through a catheter thatrequires a pressure of more than 150 mmHg on a typical 10 cc syringe toovercome the blockage. This is equal to about 0.9 lbs. of force on thesyringe plunger. It is preferable that a blockage can be overcome with apressure of less than 100 mmHg. This is equal to about 0.6 lbs. of forceon the syringe plunger. It is more preferable that a blockage can beovercome with a pressure of less than 50 mmHg, and even more preferablethat a blockage can be overcome by a pressure of 20 mmHg or less, whichis not a readily noticeable amount of pressure. Such agents includecertain liquid excipients that were found to be effective based onexperiments, which involve measuring a pressure or vacuum level inmillimeters of mercury (mmHg), as described in further detail below. Thepressure or vacuum level, referred to as the break through pressure orvacuum level, provided a quantitative measure of the formulationperformance in preventing plug formation. The liquid excipients thatwere found to be effective based on experiments at the 2% by weightlevel include, but are not limited to, glycerol, polysorbate-20, andPEG-400. The data P_(break-through) was less than 10 mmHg (pressure andvacuum) for these excipients.

Other excipients could be effective at the 2% by weight level. Theseexcipients include, but are not limited to, PEG-100, PEG-200, PEG-300,Triton X-100 (t-octylphenoxypolyethoxyethanol), Polysorbate-80,Poloxomer 124, Macrogol 15 Hydroxy Stearate, Cremophor EL (Polyoxyl 35Castor oil), and other suitable water soluble non-ionizing liquidexcipients.

Excipients could be effective at approximately the 1% by weight level.These excipients include, but are not limited to, Glycerol(conditionally acceptable, free flowing for greater than 7 days),Polysorbate-20 (similar to Glycerol), and Triton X-100.

A combination of excipients could be effective in an amount less than 2%by weight level in total. These excipients include, but are not limitedto, 1% Glycerol combined with 0.5% Polysorbate-20 (estimated to be oneof the most effective-reduced excipient concentration and performanceassurance), 1% Glycerol combined with 0.5% Triton X-100, 0.75% Glycerolcombined with 0.75% Polysorbate-20, and 0.5% Glycerol combined with 0.5%Polysorbate-20.

FIG. 1 is a view of a sphygmomanometer 10 connected to a syringe 12. Thesphygmomanometer 10 includes a gauge 14 with a visual display 16 tomeasure the pressure or vacuum level. The sphygmomanometer 10 and thesyringe 12 were used to measure the break through pressure or vacuumlevel.

Experiments

Long silicone rubber commercial catheter extension tubing segmentsspliced together, or a single small bore with a 1.5 mm inner diameterclear, and very soft laboratory silicone rubber tubing of about 15 inchin length were used for evaluation. Formulations of 30% weight pervolume (w/v) ethanol and 4% weight per weight (w/w) tri-sodium citratewith candidate biocompatible excipients were prepared and charged intothe lumens of simulated catheter tubings and capped with solid plugs.The samples were first dried near a de-humidifier for about 24 hours toallow evaporation of most ethanol before being placed into a clearpolycarbonate drying column connected in series with a large Drierite®desiccant column. The columns were also fitted with a gas flow meter anda diaphragm gas pump to provide closed loop gas circulation at about 4liter per minute (min-1). In this manner, the vertically placed modelcatheter segments were subjected to a gas stream of near zero humidityand any moisture escaped from the tubing was swept away by the flowingair stream and immediately captured by the desiccant. From time to time,when a near solid plug was observed, the sample was removed from thecolumn. Both the pressure (+) or vacuum (−) levels to cause the liquidor solid plug movement were measured when subjected to actuationmovements from a small air filled syringe 12 connected to asphygmomanometer 10. These levels are referred to as the break throughpressure or vacuum levels.

When the concentrated plug is in the liquid state, very slight pressureor vacuum level, less than 5 mmHg, caused visible movements of the plugfor dislodging. However, when the solution containing segments arecondensed into a semi-solid gel-like plug, pressure or vacuum levels ofmuch greater than 100 mmHg were required for dislodging.

Results and Discussion

Among the many water soluble and biocompatible excipients evaluated, itwas determined that solid excipients at times formed gel-like plugs,which required high break through pressures to dislodge the plugs.

The results of an experiment performed with solid excipients are shownin FIG. 2. In particular, FIG. 2 is a view of a catheter tubing 18 witha gel-like plug (crystallized sodium citrate) 20. A void 22 is left dueto evaporation and permeation of ethanol through the catheter tubing 18.FIG. 2 shows the edge 24 of the crystallization of the gel plug 26,which is a highly viscous and is formed due to highly concentratedsodium citrate that has not fully crystallized. The meniscus 28 of thefluid line is adjacent the gel plug 26. Fluid 30 is trapped between thegel plug 26 and the crystallized sodium citrate 20. A wetted portion 32of the sodium citrate crystal is located adjacent to another void 34from evaporation of ethanol. The gel-like plug 20 was formed from asolution of 30% ethanol, 4% sodium citrate, 2% polyethylene glycol-3350(PEG-3350) and 0.1% polysorbate-80 (PS-80). The break through pressureor vacuum level exceeded 140 mmHg.

Excipients which are liquid at room temperature could be quite effectivealone or in combination with another liquid excipient with surfactantproperties. In addition, surprisingly, at rather low concentrationsbelow that of the tri-sodium citrate, certain excipients which areliquid at room temperature appeared to retard or inhibit the tri-sodiumcitrate from crystallizing, making the resulting formulation flowableeven after exhaustive drying.

The results of an experiment performed with liquid excipients are shownin FIG. 3. FIG. 3 is a view of a catheter tubing 36 with a recoilingliquid/bubble 38 or recoiling air/liquid interface. An antisepticlocking solution containing 30% ethanol and 4% sodium citrate, and 2%Polysorbate-20, was subjected to rigorous drying for 12.5 days, yetremained completely fluid, and formed the recoiling liquid/bubble 24.This illustrates the effectiveness of a formulation with Polysorbate-20.

To test the hypothesis for excipients that can prevent gelation based onhydrophobic interaction with the silicone surface, we develop two newlock formulations that include excipients Polysorbate 80 and PluronicF68, respectively:

A. 30% ethanol, 4% sodium citrate, with Polysorbate 80 with twoconcentrations: 0.2% and 0.7%.

B. 30% ethanol, 4% sodium citrate, with Pluronic F68 with twoconcentrations: 0.2% and 0.7%.

When Groshong 4Fr catheters were filled with 30% ethanol, 4% sodiumcitrate, with 0.7% Polysorbate 80 and 30% ethanol, 4% sodium citrate,with 0.7% Pluronic F68 and tested for a period of 14 days, a lot ofvoids/gas bubbles were observed in the first days (FIG. 4). The questionwas what are the bubbles and do they affect the occlusion of thecatheter. Gas bubbles were observed in all three Groshong cathetersfilled with 30% ethanol, 4% sodium citrate, with 0.7% Polysorbate 80,and 30% ethanol, 4% sodium citrate, with 0.7% Pluronic F68,respectively, in the in vitro aqueous bath with vascular flowsimulation. After 14 days there were no voids/bubbles in the segment ofthe catheter immersed into the water and the solution line wascontinuous, while the whole dry segment was empty (FIG. 5).

An in vitro test evaluated catheter lock formulations containing 0.2%additives: 30% ethanol, 4% sodium citrate, with 0.2% Polysorbate 80, and30% ethanol, 4% sodium citrate, with 0.2% Pluronic F68. There were novoids/gas gaps when Per-Q-Cath 4F catheters were subjected to in vitrosimulation bath for 12 days without changing the solution. Catheterswith 30% ethanol, 4% sodium citrate, with 0.2% Polysorbate 80, and 30%ethanol, 4% sodium citrate, with 0.2% Pluronic F68, and a lock solutionof 30% ethanol, 4% sodium citrate with 0.5% Polysorbate 20 and 1% ofGlycerol had <20 mmHg pressure after 12 days in vitro in water bath @37° C. These formulations had better performance than lock solutionwithout excipients (control). Per-Q-Cath catheters filled with thecontrol lock solution at pressure greater than 300 mmHg when subjectedto the same conditioning.

Based on the results from the preliminary in vitro study of Groshong 4Frand Per-Q-Cath 4Fr catheters, an extensive experiment was conductedusing four formulations:

-   -   Lock Solution Control (30% ethanol, 4% sodium citrate)    -   30% ethanol, 4% sodium citrate, with 0.2% Polysorbate 80    -   30% ethanol, 4% sodium citrate, with 0.2% Pluronic F68    -   a lock solution of 30% ethanol, 4% sodium citrate with 0.5%        Polysorbate 20 and 1% of Glycerol        and three different types of silicone catheters: Per-Q-Cath 4Fr,        Broviac 4.2Fr, and Hickman 10Fr. The goal of this study was to        evaluate the effect of these formulations on the pressure for        three different types of silicone catheters after 14 days in        saline baths @ 37° C. Catheters were divided into three groups        and tested in three baths filled with saline @ 37° C. Catheters        were refilled with fresh formulations after each round of 14        days (total three rounds of 14 days each).

Results indicated that catheters filled with a lock solution of 30%ethanol, 4% sodium citrate with 0.5% Polysorbate 20 and 1% of Glycerolformulation had the lowest pressure measurements. Formulation with 30%ethanol, 4% sodium citrate, with Polysorbate 80 also performed well.

Another approach that was considered to improve the performance of thelock formulation was to increase the percentage of the additives. Basedon the prior results, three formulations were selected:

-   -   30% ethanol, 4% sodium citrate with 0.5% Polysorbate 20 and 1.5%        Glycerol    -   30% ethanol, 4% sodium citrate with 2% Glycerol    -   30% ethanol 4% sodium citrate with 2% Polysorbate 80        Results from the first round of 14 days are presented in Table        3.        Table 3. Pressure measurements of catheters subjected to in        vitro testing filled with formulations with 2% additives. Note        Hickman has three lumens indicated by white (w), blue (b), and        red (r), which indicate the respective size of each lumen.

Pressure (mmHg) Sample Description 1^(st) round of 14 days 28-1H Hickmanwith 30% ethanol, 4% sodium w- <20 b-<20 r-<20 citrate with 0.5%Polysorbate 20 and 1.5% Glycerol 28-2H Hickman with 30% ethanol, 4%sodium w- 40 b-<20 r-<20 citrate with 2% Glycerol 28-3H Hickman with 30%ethanol 4% sodium w- 28 b- 80 r- <20 citrate with 2% Polysorbate 8028-1B Broviac with 30% ethanol, 4% sodium 60 citrate with 0.5%Polysorbate 20 and 1.5% Glycerol 28-2B Broviac with 30% ethanol, 4%sodium 52 citrate with 2% Glycerol 28-3B Broviac with 30% ethanol 4%sodium 58 citrate with 2% Polysorbate 80 28-1P Per-Q-Cath with 30%ethanol, 4% <20 sodium citrate with 0.5% Polysorbate 20 and 1.5%Glycerol 28-2P Per-Q-Cath with 30% ethanol, 4% <20 sodium citrate with2% Glycerol 28-3P Per-Q-Cath with 30% ethanol 4% 42 sodium citrate with2% Polysorbate 80 1A-H Hickman with 30% ethanol, 4% sodium w- <20 b- 30r-<20 citrate with 0.5% Polysorbate 20 and 1.5% Glycerol 2A-H Hickmanwith 30% ethanol, 4% sodium w- 36 b- 26 r-<20 citrate with 2% Glycerol3A-H Hickman with 30% ethanol 4% sodium w- <20 b- <20 r-<20 citrate with2% Polysorbate 80 1B-H Hickman with 30% ethanol, 4% sodium w- <20 b- 22r-<20 citrate with 0.5% Polysorbate 20 and 1.5% Glycerol 2B-H Hickmanwith 30% ethanol, 4% sodium w- 46 b- 50 r-<20 citrate with 2% Glycerol3B-H Hickman with 30% ethanol 4% sodium w- 130 b- <20 r-<20 citrate with2% Polysorbate 80 1A-B Broviac with 30% ethanol, 4% sodium <20 citratewith 0.5% Polysorbate 20 and 1.5% Glycerol 2A-B Broviac with 30%ethanol, 4% sodium <20 citrate with 2% Glycerol 3A-B Broviac with 30%ethanol 4% sodium 42 citrate with 2% Polysorbate 80 1B-B Broviac with30% ethanol, 4% sodium 30 citrate with 0.5% Polysorbate 20 and 1.5%Glycerol 2B-B Broviac with 30% ethanol, 4% sodium 28 citrate with 2%Glycerol 3B-B Broviac with 30% ethanol 4% sodium 92 citrate with 2%Polysorbate 80 1-P Per-Q-Cath with 30% ethanol, 4% 34 sodium citratewith 0.5% Polysorbate 20 and 1.5% Glycerol 2-P Per-Q-Cath with 30%ethanol, 4% 24 sodium citrate with 2% Glycerol 3-P Per-Q-Cath with 30%ethanol 4% 105 sodium citrate with 2% Polysorbate 80Results from the first measurements are in favor for the formulationswith Glycerol.

While the disclosure has been described in terms of specificembodiments, it is evident in view of the foregoing description thatnumerous alternatives, modifications and variations will be apparent tothose skilled in the art. Accordingly, the disclosure is intended toencompass all such alternatives, modifications and variations which fallwithin the scope and spirit of the disclosure.

What is claimed is:
 1. A locking composition for a catheter comprising:at least one lower alcohol; at least one functional compound; and atleast one excipient at a sufficient concentration to prevent occlusionof the catheter.
 2. The locking composition of claim 1, wherein the atleast one functional compound is at least one anti-coagulant.
 3. Thelocking composition of claim 1, wherein the at least one functionalcompound is at least one anti-microbial.
 4. The locking composition ofclaim 1, wherein the at least one functional compound is at least oneantibiotic.
 5. The locking composition of claim 1, wherein the at leastone lower alcohol is present in the amount of about 30% by weight of thelocking composition.
 6. The locking composition of claim 2, wherein theat least one anti-coagulant compound is present in the amount of about4% by weight of the locking composition.
 7. The locking composition ofclaim 1, wherein the at least one excipient is present in the amount ofat least about 0.5% by weight of the locking composition.
 8. The lockingcomposition of claim 7, wherein the at least one excipient is at leastone liquid excipient.
 9. The locking composition of claim 1, wherein theat least one liquid excipient is selected from PEG-100, PEG-200,PEG-300, Triton X-100, Polysorbate-80, Poloxomer 124, Macrogel 15Hydroxy Stearate, Cremophor EL, and combinations thereof.
 10. Thelocking composition of claim 2, wherein the at least one anti-coagulantcompound is sodium citrate.
 11. A locking composition for an implantablecatheter comprising: a lower alcohol; an anti-coagulant compound; and anexcipient, wherein the excipient is present in the amount of at leastabout 0.5% by weight of the locking composition.
 12. The lockingcomposition of claim 11, wherein the lower alcohol is selected from thegroup consisting of ethanol, proponal, isopropanol, butanol, andcombinations thereof.
 13. The locking composition of claim 11, whereinthe anti-coagulant compound is selected from the group consisting ofriboflavin, sodium citrate, ethylene diamine tetraacetic acid, heparin,lower molecular weight heparin, citric acid, and combinations thereof.14. The locking composition of claim 11, further comprising ananti-microbial compound selected from the group consisting oftaurolidine, triclosan, chlorhexidine, gentamicin, vancomycin, andcombinations thereof.
 15. The locking composition of claim 11, whereinthe excipient is a liquid.
 16. The locking composition of claim 15,wherein the liquid excipient is a water soluble, non-ionizing liquidexcipient.
 17. The locking composition of claim 15, wherein the liquidexcipient is selected from PEG-100, PEG-200, PEG-300, Triton X-100,Polysorbate-80, Poloxomer 124, Macrogel 15 Hydroxy Stearate, CremophorEL, and combinations thereof.
 18. The locking composition of claim 15,wherein the liquid excipient is selected from glycerol, polysorbate-20,and Triton X-100.
 19. The locking composition of claim 15, wherein theliquid excipient comprises a combination of excipients, wherein thecombination of excipients is present in the amount of at least about 1%by weight of the locking composition.
 20. The locking composition ofclaim 19, wherein the combination of excipients is selected from thegroup consisting of: a. glycerol present in the amount of about 1% byweight of the locking composition and polysorbate-20 present in theamount of about 0.5% by weight of the locking composition; b. glycerolpresent in the amount of about 1% by weight of the locking compositionand Triton X-100 present in the amount of about 0.5% by weight of thelocking composition; c. glycerol present in the amount of about 0.75% byweight of the locking composition and polysorbate-20 present in theamount of about 0.75% by weight of the locking composition; and d.glycerol present in the amount of about 0.5% by weight of the lockingcomposition and polysorbate-20 present in the amount of about 0.5% byweight of the locking composition.
 21. A method of preventingcrystallization in an implantable catheter comprising: introducing alocking composition into a lumen of the implantable catheter, whereinthe locking composition comprises: a lower alcohol; an anti-coagulantcompound; and an excipient, wherein the excipient is present in theamount of at least about 0.5% by weight of the locking composition. 22.The method of claim 21, wherein the excipient of the locking compositionis selected from the group consisting of glycerol, polysorbate-20,PEG-400, and combinations thereof.
 23. The method of claim 21, whereinthe excipient of the locking composition is selected from the groupconsisting of glycerol, polysorbate-20, Triton X-100, and combinationsthereof.
 24. The method of claim 21, wherein the excipient of thelocking composition comprises a combination of excipients present in theamount of at least about 0.5% by weight of the locking combination,wherein the combination of excipients is selected from: a. glycerolpresent in the amount of about 1% by weight of the locking compositionand polysorbate-20 present in the amount of about 0.5% by weight of thelocking composition; b. glycerol present in the amount of about 1% byweight of the locking composition and Triton X-100 present in the amountof about 0.5% by weight of the locking composition; c. glycerol presentin the amount of about 0.75% by weight of the locking composition andpolysorbate-20 present in the amount of about 0.75% by weight of thelocking composition; and d. glycerol present in the amount of about 0.5%by weight of the locking composition and polysorbate-20 present in theamount of about 0.5% by weight of the locking composition.
 25. Thelocking composition of claim 11 wherein the lower alcohol is ethanol,the anti-coagulant is sodium citrate and the excipient comprisespolysorbate-20 and glycerol.
 26. The locking composition of claim 25wherein polysorbate-20 comprises at least 0.5% by weight and glycerolcomprises at least 1.5% by weight.